The long-range objective of this project is the detailed molecular characterization of the Na+/I-symporter (NIS), a key transport protein that catalyzes the active translocation of iodide into the thyroid gland. In the previous funding periods, considerable progress has been made on this project. A cDNA encoding the NIS has been cloned, and functionally expressed in oocytes and COS cells. A structural model for the NIS has been proposed, and the first anti-NIS antibodies have been generated. In addition, electrophysiological analysis of NIS has been carried out in oocytes, and the importance of the aspartic acid #16 residue in NIS function has been investigated. The specific aims of the present application are: 1) to continue the identification of functionally important amino acid residues and domains of NIS and investigate its topology in the plasma membrane, 2) to elucidate the biogenesis and regulatory mechanisms of NIS, and 3) to explore possible homologies between iodine transporters from different tissues, including the extra-thyroidal iodine accumulation systems present in the salivary gland and gastric mucosa.